Original Article
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World J Hepatol. Feb 27, 2014; 6(2): 72-84
Published online Feb 27, 2014. doi: 10.4254/wjh.v6.i2.72
Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats
Tomohide Hori, Shinji Uemoto, Feng Chen, Lindsay B Gardner, Ann-Marie T Baine, Toshiyuki Hata, Takayuki Kogure, Justin H Nguyen
Tomohide Hori, Shinji Uemoto, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
Feng Chen, Lindsay B Gardner, Ann-Marie T Baine, Toshiyuki Hata, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
Takayuki Kogure, Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan
Justin H Nguyen, Division of Transplant Surgery, Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, United States
Author contributions: Hori T and Hata T performed the surgery and collected the data; Hori T wrote this paper; Chen F, Gardner LB and Baine AMT performed the assays; Kogure T helped to perform the protein assays; Nguyen JH and Uemoto S designed this study and supervised this research.
Supported by Grants to Nguyen JH from the Deason Foundation, Sandra and Eugene Davenport, Mayo Clinic CD CRT-II partially; the Uehara Memorial Foundation to Hori T, Tokyo 171-0033, Japan, No. 200940051
Correspondence to: Tomohide Hori, MD, PhD, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. horit@kuhp.kyoto-u.ac.jp
Telephone: +81-75-7513111 Fax: +81-75-7513106
Received: July 30, 2013
Revised: December 8, 2013
Accepted: January 13, 2014
Published online: February 27, 2014
Abstract

AIM: To investigate oxidative stress (OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage.

METHODS: Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant (60% hepatectomy); orthotopic liver transplantation (OLT) with whole liver graft (100% OLT); and split OLT (SOLT) with 40% graft (40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OS-induced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase (PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography.

RESULTS: Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT.

CONCLUSION: Under conditions with an insufficient liver remnant, prevention of OS-induced damage via the Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery.

Keywords: Free radicals, Akt, Phosphatidylinositol 3-kinase, Matrix metalloproteinase, Tissue inhibitors of metalloproteinase

Core tip: Although shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery, these injuries also cause fatal liver damage. Postoperative liver damage is still a critical matter in the field of liver surgery. Oxidative stress and extracellular matrices are important for liver regeneration after surgery and these may be important keys to overcome current problems in the field of liver surgery. Here, we investigated oxidative stress-mediated damage and the behavior of extracellular matrices in various rat models with liver surgery.